Genetic Variant SFTPC:c.-67C>T (chr8-22161762-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000318561.7(SFTPC):c.-67C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,613,618 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

SFTPC
ENST00000318561.7 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.11

Publications

1 publications found

Variant links:

Genes affected

SFTPC (HGNC:10802): (surfactant protein C) This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.[provided by RefSeq, Feb 2010]

SFTPC Gene-Disease associations (from GenCC):

SFTPC-related interstitial lung disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
surfactant metabolism dysfunction, pulmonary, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
chronic respiratory distress with surfactant metabolism deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SFTPC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-22161762-C-T is Benign according to our data. Variant chr8-22161762-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 362547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000414 (63/152284) while in subpopulation AMR AF = 0.00098 (15/15306). AF 95% confidence interval is 0.000604. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 63 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000318561.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
SFTPC	NM_001385654.1	c.-53-14C>T	intron	N/A	NP_001372583.1	A0A0S2Z4Q0
SFTPC	NM_001385655.1	c.-53-14C>T	intron	N/A	NP_001372584.1	A0A0S2Z4Q0
SFTPC	NM_001385656.1	c.-53-14C>T	intron	N/A	NP_001372585.1	P11686-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SFTPC	ENST00000318561.7	TSL:1	c.-67C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000316152.3	P11686-1
SFTPC	ENST00000318561.7	TSL:1	c.-67C>T	5_prime_UTR	Exon 1 of 6	ENSP00000316152.3	P11686-1
SFTPC	ENST00000950317.1		c.-67C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000620376.1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000269

AC:

AN:

249126

AF XY:

0.000266

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000242

AC:

354

AN:

1461334

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33478

American (AMR)

AF:

0.000693

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000186

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53092

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000220

AC:

245

AN:

1111858

Other (OTH)

AF:

0.000679

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000414

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41568

American (AMR)

AF:

0.000980

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68024

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000612

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Interstitial lung disease 2 (1)

not provided (1)

Surfactant metabolism dysfunction, pulmonary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.9

(source)

DANN

Benign

0.41

PhyloP100

-1.1

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over