Genetic Variant SFTPC:c.-91C>T (chr8-22161738-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000318561.7(SFTPC):c.-91C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00988 in 1,612,608 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0069 ( 8 hom., cov: 32)

Exomes 𝑓: 0.010 ( 114 hom. )

Consequence

SFTPC
ENST00000318561.7 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.0580

Publications

2 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 8-22161738-C-T is Benign according to our data. Variant chr8-22161738-C-T is described in ClinVar as Benign. ClinVar VariationId is 362546.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00687 (1046/152294) while in subpopulation NFE AF = 0.0108 (734/68018). AF 95% confidence interval is 0.0101. There are 8 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1046 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.-53-38C>T	intron	N/A	NP_001372583.1	A0A0S2Z4Q0
SFTPC	NM_001385655.1	c.-53-38C>T	intron	N/A	NP_001372584.1	A0A0S2Z4Q0
SFTPC	NM_001385656.1	c.-53-38C>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.-91C>T	5_prime_UTR	Exon 1 of 6	ENSP00000316152.3	P11686-1
SFTPC	ENST00000950317.1		c.-91C>T	5_prime_UTR	Exon 1 of 4	ENSP00000620376.1
SFTPC	ENST00000905727.1		c.-91C>T	5_prime_UTR	Exon 1 of 4	ENSP00000575786.1

Frequencies

GnomAD3 genomes

AF:

0.00687

AC:

1046

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00705

AC:

1753

AN:

248564

AF XY:

0.00679

show subpopulations

Gnomad AFR exome

AF:

0.00310

Gnomad AMR exome

AF:

0.00765

Gnomad ASJ exome

AF:

0.00845

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00893

GnomAD4 exome

AF:

0.0102

AC:

14894

AN:

1460314

Hom.:

114

Cov.:

AF XY:

0.0100

AC XY:

7266

AN XY:

726356

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33458

American (AMR)

AF:

0.00796

AC:

356

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00934

AC:

244

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00166

AC:

143

AN:

86176

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

52764

Middle Eastern (MID)

AF:

0.00214

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.0121

AC:

13478

AN:

1111508

Other (OTH)

AF:

0.00823

AC:

496

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

759

1518

2278

3037

3796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

512

1024

1536

2048

2560

<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:

0.00687

AC:

1046

AN:

152294

Hom.:

Cov.:

AF XY:

0.00616

AC XY:

459

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41568

American (AMR)

AF:

0.00876

AC:

134

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

734

AN:

68018

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00823

Hom.:

Bravo

AF:

0.00785

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Interstitial lung disease 2 (1)

Surfactant metabolism dysfunction, pulmonary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.7

(source)

DANN

Benign

0.66

PhyloP100

0.058

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=297/3

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