10-79942454-G-C

Variant names:

• chr10-79942454-G-C
• rs17878336
• NM_003019.5:c.367C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003019.5(SFTPD):​c.367C>G​(p.Leu123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,613,350 control chromosomes in the GnomAD database, including 1,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.026 (87 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1025 hom.)
• Consequence: SFTPD NM_003019.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.483

Genes affected

SFTPD (HGNC:10803): (surfactant protein D) The protein encoded by this gene is part of the innate immune response, protecting the lungs against inhaled microorganisms and chemicals. The encoded protein may also be involved in surfactant metabolism. [provided by RefSeq, Jul 2015]

ENSG00000283913 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068519413).
• BP6: Variant 10-79942454-G-C is Benign according to our data. Variant chr10-79942454-G-C is described in ClinVar as [Benign]. Clinvar id is 165216.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 = 0.0265 (4026/152196) while in subpopulation AMR AF= 0.0451 (690/15288). AF 95% confidence interval is 0.0423. There are 87 homozygotes in gnomad4. There are 1913 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 87 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPD	NM_003019.5	c.367C>G	p.Leu123Val	missense_variant	Exon 4 of 8	ENST00000372292.8	NP_003010.4
SFTPD	XM_011540087.2	c.367C>G	p.Leu123Val	missense_variant	Exon 4 of 8		XP_011538389.1
SFTPD	XM_011540088.3	c.316+309C>G		intron_variant	Intron 3 of 6		XP_011538390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPD	ENST00000372292.8	c.367C>G	p.Leu123Val	missense_variant	Exon 4 of 8	1	NM_003019.5	ENSP00000361366.3

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4029 AN: 152076 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0307

GnomAD3 exomes AF: 0.0257 AC: 6461 AN: 251036 Hom.: 120 AF XY: 0.0257 AC XY: 3494 AN XY: 135690

Gnomad AFR exome AF: 0.00770

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0350

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00921

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0346 AC: 50500 AN: 1461154 Hom.: 1025 Cov.: 32 AF XY: 0.0339 AC XY: 24649 AN XY: 726780

Gnomad4 AFR exome AF: 0.00547

Gnomad4 AMR exome AF: 0.0260

Gnomad4 ASJ exome AF: 0.0376

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00922

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0398

Gnomad4 OTH exome AF: 0.0329

GnomAD4 genome AF: 0.0265 AC: 4026 AN: 152196 Hom.: 87 Cov.: 32 AF XY: 0.0257 AC XY: 1913 AN XY: 74416

Gnomad4 AFR AF: 0.00734

Gnomad4 AMR AF: 0.0451

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.0377

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.0342 Hom.: 71

Bravo AF: 0.0271

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0409 AC: 352

ExAC AF: 0.0256 AC: 3105

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0372

EpiControl AF: 0.0381

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu123Val in exon 4 of SFTPD: This variant is not expected to have clinical sign ificance because it has been identified in 4.1% (352/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs17878336). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.029
DANN	Benign	0.93
DEOGEN2	Benign	0.085	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.74	T;D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.015	N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.023
Sift	Benign	0.15	T;T
Sift4G	Benign	0.29	T;.
Polyphen		0.017	B;.
Vest4		0.086
MPC		0.17
ClinPred		0.0085	T
GERP RS		-6.7
Varity_R		0.043
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17878336; hg19: chr10-81702210;