rs2243639

chr10-79941966-T-Cchr10-79941966-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003019.5(SFTPD):c.538A>G(p.Thr180Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,605,800 control chromosomes in the GnomAD database, including 325,312 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.71 (39961 hom., cov: 32)
  • Exomes 𝑓: 0.62 (285351 hom.)
• Consequence: SFTPD NM_003019.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.00

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.466303E-6).
• BP6: Variant 10-79941966-T-C is Benign according to our data. Variant chr10-79941966-T-C is described in ClinVar as [Benign]. Clinvar id is 165215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPD	NM_003019.5	c.538A>G	p.Thr180Ala	missense_variant	5/8	ENST00000372292.8
SFTPD	XM_011540087.2	c.538A>G	p.Thr180Ala	missense_variant	5/8
SFTPD	XM_011540088.3	c.421A>G	p.Thr141Ala	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPD	ENST00000372292.8	c.538A>G	p.Thr180Ala	missense_variant	5/8	1	NM_003019.5	P1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107888 AN: 151984 Hom.: 39889 Cov.: 32

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.693

GnomAD3 exomes AF: 0.657 AC: 164431 AN: 250320 Hom.: 55263 AF XY: 0.655 AC XY: 88685 AN XY: 135300

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.809

Gnomad SAS exome AF: 0.726

Gnomad FIN exome AF: 0.605

Gnomad NFE exome AF: 0.601

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.623 AC: 905035 AN: 1453698 Hom.: 285351 Cov.: 33 AF XY: 0.625 AC XY: 452022 AN XY: 723626

Gnomad4 AFR exome AF: 0.942

Gnomad4 AMR exome AF: 0.616

Gnomad4 ASJ exome AF: 0.638

Gnomad4 EAS exome AF: 0.758

Gnomad4 SAS exome AF: 0.726

Gnomad4 FIN exome AF: 0.608

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.654

GnomAD4 genome AF: 0.710 AC: 108028 AN: 152102 Hom.: 39961 Cov.: 32 AF XY: 0.711 AC XY: 52826 AN XY: 74350

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.790

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.697

Alfa AF: 0.619 Hom.: 69275

Bravo AF: 0.723

TwinsUK AF: 0.590 AC: 2188

ALSPAC AF: 0.612 AC: 2358

ESP6500AA AF: 0.924 AC: 4070

ESP6500EA AF: 0.610 AC: 5243

ExAC AF: 0.663 AC: 80494

Asia WGS AF: 0.790 AC: 2748 AN: 3478

EpiCase AF: 0.605

EpiControl AF: 0.598

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 18, 2013	Benign based on population frequency. There are a few association studies that claim a role in diseases unrelated to germline pulmonary diseases -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 30013576, 16741161, 21790524) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.19
Dann	Benign	0.52
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.23	T;T
MetaRNN	Benign	0.0000025	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.40	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.63	N;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;T
Sift4G	Benign	0.86	T;.
Polyphen		0.0	B;.
Vest4		0.010
MPC		0.17
ClinPred		0.0079	T
GERP RS		-3.8
Varity_R		0.046
gMVP		0.098

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: rs2243639; hg19: chr10-81701722; COSMIC: COSV64853510;